The use of neuroimaging in the diagnosis of mitochondrial disease

Abstract

Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease.

Neuroimaging in Mitochondrial Disorders

“…Neuroimaging has already shown its potential for the investigation and management of patients with mitochondrial disorders allowing clinicians and researchers to study the timing, extent, and potential of reversibility of neural injury [9], and in many cases providing noninvasive and repeatable biomarker inquiry. The term "neuroimaging" now encompasses many investigative modalities beyond routine T1 and T2 imaging, including volumetric analysis, diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), arterial spin labeling, and functional magnetic resonance imaging (fMRI).…”

“…Among child neurologists, bilateral lesions in the putamen and basal ganglia nuclei are recognized as being the sin qua non and most prevalent feature of many mitochondrial syndromes [8,9,27] (Fig. 4).…”

“…Mitochondrial-associated brain injury patterns are often characterized by whether the process primarily involves gray matter, white matter, or both, and beyond that, whether subcortical or cortical gray matter nuclei are involved [8]. Although expected to be global insults due to impaired energy metabolism, some mitochondrial disorders result in selective injury to deep gray matter nuclei or white matter, whereas others have patterns of cerebellar atrophy or strokes in nonvascular territories [9]. Selectivity for particular brain regions or even cell types based on morphology or neurotransmitter systems (astrocytes/neuron: glutamatergic, Gamma-aminobutyric acid (GABA)-ergic) remains poorly understood, as is the case in other inborn errors of metabolism.…”

A patient with congenital hyperlactataemia and Leigh syndrome: an uncommon mitochondrial variant

“…Leigh syndrome, also known as subacute necrotising encephalomyelopathy, is characterised by focal, bilateral, symmetrical deep grey nuclei lesions particularly involving basal ganglia and periaqueductal grey matter. 6 Most patients have varying degrees of encephalopathy, basal ganglia, and brainstem dysfunction. Similar to all mitochondrial disorders, Leigh syndrome is genetically heterogeneous but some subtypes are known to be more common.…”

Tract-Based Spatial Statistical Analysis of Diffusion Tensor Imaging in Pediatric Patients with Mitochondrial Disease: Widespread Reduction in Fractional Anisotropy of White Matter Tracts

“…itochondrial diseases [1][2][3] represent a heterogeneous group of disorders defined by impairment of oxidative phosphorylation. These can manifest in virtually any tissue, often with predominant involvement of the central nervous system.…”